DESCRIPTION Rather than severing the cord, most traumatic spinal injuries contuse the cord, leaving a portion of nervous tissue intact (Bunge et al., 1993; Kakulas, 1987). Roughly half of people with spinal cord injury (SCI) retain at least some ability to move voluntarily below the injury level. Even people without conscious sensation or movement below their injury often retain a degree of intact circuitry traversing the lesion (Sherwood et al., 1992) - but they may not be able to consciously control those circuits. This unfortunate irony stems from the fact that the nerve fibers controlling most voluntary movements, known as the corticospinal tract, are the least likely to survive across spinal injuries. The fibers most likely to partially withstand SCI originae in the brainstem - the lower, mostly subconscious part of the brain. If detour connections could be established between cortical and brainstem motor pathways above spinal lesions, then patients could use spared brainstem fibers to regain conscious control over muscles below their injuries. We wil use targeted physical exercises to strengthen these types of detour connections. Our exercise strategy exploits the principle of Hebbian plasticity, known coloquially as 'Fire Together, Wire Together': When nearby neurons fire together repeatedly, connections between those neurons strengthen. We will demonstrate this approach in veterans with chronic, 'motor incomplete' thoracic SCI - those who have full use of their hands and at least slight ability to move their legs. Participants will undergo a balance-training program (to stimulate brainstem circuits) while simultaneously performing skilled hand exercises (to stimulate corticospinal circuits). We will compare the effects of this multimodal Hebbian exercise program to that of 'traditional' weight-supported treadmill training on the transmission of neural signals between the brain and leg muscles across spinal lesions. We will also assess multiple other parameters to understand the neural mechanisms underlying functional changes in response to treatment. We hypothesize that individuals with chronic thoracic SCI undergoing multimodal training imultaneously stimulating cortical and brainstem pathways above spinal lesions will show improved neural conductivity across spinal lesions compared with patients undergoing treadmill training. Prior to this application, the candidate, Dr. Noam Y. Harel, spent his entire research career performing basic bench science involving molecular mechanisms and animal models of motor neuron disease and spinal cord injury. He is now transitioning to clinical research with the goal of translating his findings from the laboratory into improved clinical neurorehabilitation outcomes. To make this transition successful, he needs mentoring in the use of electrophysiological techniques for assessing changes in spared neural circuits. He also needs mentoring and protected time in order to become proficient in the logistics of clinical trial design, human subject recruitment and safety, and the management and interpretation of clinical trial data. Dr. Harel has found the optimal mentor and environment for making this transition - his primary mentor will be Dr. Ann M. Spungen of the RR&D National Center of Excellence for the Medical Consequences of Spinal Cord Injury. She has 22 years of experience conducting and publishing SCI-related clinical research, and in mentoring past and current investigators. Aside from being well-funded, well-equipped, and newly renovated, the Center has multiple other experienced and helpful members able to assist Dr. Harel as he establishes himself. Dr. Harel's secondary mentor will be Dr. Seth L. Pullman, Professor of Neurology and Director of the Clinical Motor Physiology Laboratory at Columbia University. He is a leading expert in clinical research using electrophysiological techniques such as evoked potentials, electromyography, and transcranial magnetic stimulation. Dr. Pullman will ensure that Dr. Harel receives thorough training and expertise in these techniques. PUBLIC HEALTH RELEVANCE: A growing number of veterans live with spinal cord injury (SCI). Exercise rehabilitation provides many benefits at all stages of SCI, whether it happened two weeks ago or 20 years ago. Most exercise programs focus on keeping muscles strong and flexible, not usually on helping patients control their muscles. This study will identify which nerve circuits still have potential to be stimulated. An exercise program will then be applied that focuses on regaining conscious control of muscles below the injury. This exercise program is safe and does not require expensive equipment. If it works, the program would be easy to expand to other VA and non-VA centers around the world. A similar approach could be used for other neurological conditions such as stroke or traumatic brain injury. Finally, exercise-based treatment can be combined with drug or cell-based treatments to potentially produce even larger benefits on neurorecovery.!